Ornithine derived Alkaloids Tropane Alkaloids

VI. Alkaloids of the Tropane group There are two important types of tropane alkaloids: They all possess the tropane nucleus. 3

Being esters, they are unstable towards acid and alkali. Bicyclic system made up of a 5-membered ring (1, N, 5, 6, and 7) and a 6-membered ring (1, 2, 3, 4, 5, N). N is common to both. The nucleus always carries an oxygen in position 3. The nitrogen is always methylated. The oxygen is substituted with an aromatic acid, therefore , creating an ester. 1 5 Being esters, they are unstable towards acid and alkali.

a) Solanaceous alkaloids: Datura stramonium Hyoscyamus niger Atropa belladonna

Solanaceous alkaloids come from the solanaceae (tomato and potato). Some of the alkaloids they produce are: Atropine Hyoscyamine Hyoscine Hyoscyamine is the pure optical isomer; (+)Hyoscyamine, (-)Hyoscyamine. Atropine is the racemic of hyoscyamine. Atropine = (±)Hyoscyamine.

The 3-hydroxy derivative of tropane is known as TROPINE. Esterification of tropine with tropic acid yields hyoscyamine (tropine tropate) 3 TROPANE TROPINE TROPIC ACID

Atropine & Hypscyamine Hyoscyamine is the major natural alkaloid with negative optical rotation (l- form). During extraction hyoscyamine racemizes to the optically inactive dl Atropine. Both alkaloids composed of tropine base and tropic acid.

Pharmacological actions and uses of Atropine Atropine sulfate has an anti-cholinergic effect (parasympatholytic activity). It is used in medicine as: A mydriatic (causes dilatation of the eye pupil). An antispasmodic (relaxes the intestinal and bronchial smooth muscles). A pre-anesthetic medication to stop body secretions. A CNS stimulant. An antidote to organophosphorus insecticides.

Hyoscine (Scopolamine) Hyoscine is an ester of l-tropic acid with scopoline base. Hyoscine is a syrupy liquid.

Effects and uses of Scopolamine (Hyoscine): The action of Scopolamine (Hyoscine) differs from that of Atropine and Hyoscyamine in: → It has no central nervous system stimulation effect, but in high doses it causes hallucination. Hyoscine HBr is commonly used in as sedative Has antiemetic effect N.B. Vitalis test is a special test for solanaceous alkaloids + conc HNO3 & alc. KOH violet colour

Synthetic and Semisynthetic Derivatives: Homatropine: Synthetic drug prepared by passing HCl gas in a mixture of tropine base and mandelic acid in the presence of water. Homatropine is less toxic than Atropine. It is hypnotic in small doses. Homatropine is used as Mydriatic with shorter effect than Atropine.

Quaternary Semisynthetic derivative of Hyscine. Hyoscine butyl bromide: Quaternary Semisynthetic derivative of Hyscine. It is used as antispasmodic and antiemetic.

b- Erythroxylon (Coca) Alkaloids Occurrence: Coca leaves contain about 2% total alkaloids. Main Alkaloids are: 1- Cocaine. 2- Cinnamylcocaine. 3. a- truxilline. The base for Coca Alakloid is called “Ecogonine”

Cocaine It is the major Alkaloid in Coca leaves. Cocaine is diester Alkaloid. Heating at 160 0C in conc. HCl leads to hydrolyses of cacaine to MeOH, Benzoic acid and Ecogonine base.

Uses: Cocaine was used as local anesthetic. Cocaine has a CNS stimulant activity so is one of the widely abused drugs.

Alkaloids derived from Glycine Purine Alkaloids

Purine alkaloids Purines are derivatives of a heterocyclic nucleus consisting of a six-membered Pyrimidine ring fused to a five-membered Imidazole ring. Purines are Psudo alkaloids (Are not derived from amino acids but have nitrogen in a heterocyclic ring) The pharmaceutically important bases of this group are all methylated derivatives of 2,6 dioxy-purine (Xanthine). These alkaloids are weak bases, they give no precipitate with Mayer's reagent.

Purine alkaloids xanthine coffeine theobromine theophyilline They are all methyl derivatives of xanthine.

caffeine and theophylline are used in therapeutics 1,3,7-trimethylxanthine Tea leaves (2- 5%), Coffee seeds (1-2 %), Cola leaves (2- 3%), Gurana seeds (2.5- 5 %) and Cacao seeds, (0.2- 0.5 %). White powder, bitter taste, very weak base, soluble in hot water, in alcohol and CHCl3, sparingly in ether. Sublimable. Doesn’t precipitate with Mayer’s reagent Theophyline 1,3-dimethylxanthine Traces in Tea leaves White, odorless, bitter crystalline, soluble in H2O, alcohol Sparingly soluble in ether and CHCl3 Theobromine 3,7-dimethylxanthine (mainly in seeds of Theobroma cacao ) White, odorless, bitter crystalline, sparingly soluble H2O Insoluble in ether Sublimable caffeine and theophylline are used in therapeutics

Pharmacology Identification: Caffeine ► stimulation of CNS, effect on the psychic centers ► Causes flow of thought, lessen drowsiness, relieve headaches and gives a sense of comfort and well-being Theobromine ► Diuretic effect and used in the treatment of various types of edema Theophylline ► smooth muscle relaxant, myocardial stimulant and diuretic Identification: Murexide reaction Alkaloids + H2O2 + HCl gives after evaporation yellow-red color which turns to red-violet upon addition of NH3.

Color tests: Murexide test: (caffeine, theobromine and theophylline). Crystals of caffeine + drops of concentrated HCl and traces of KClO3 →evaporated on water bath → red color is produced wich turns to violet on exposure to ammonia vapor. Tannic acid test: (caffeine and theophylline): A concentrated solution of the alkaloid + tannic acid → white precipitate is obtained that dissolves in excess of the reagent. Ferrous sulfate test: (theobromine): To a solution of the alkaloid + drops of concentrated HCl + few drops of Br2­ water + a drop of FeSO4 + few drops of ammonia → Blue color.

Steroidal Alkaloids These contain the perhydrocyclopentano-phenanthrene skeleton characteristic of sterols. They usually occur in glycosidal combination with sugars and thus called glucoalkaloids e.g. Solanum and Veratrum alkaloids.

1- Solanum alkaloids Occurrence: They occurs in Solanum spp. Consitituents: Solanine, Solasonine. Properties: They are glucoalklaloids with a sugar parts. Uses: 1- The aglycone of both alkaloids are used as a starting material for the synthesis of steroidal drugs. 2- Solasonine is used as agricultural insecticide.

2- Veratrum alkaloids They are of two types: 1- Typical or atypical steroidal alkamines containing one or two non estrified hydroxyl groups e.g. Rubijervine and Veratramine. 2- Highly oxygenated alkamines estrified with organic acids e.g. Protoveratrines A& B. Uses: The second group posses hypotensive effect.

Diterpene Alkaloids Taxol Occurrence: Barks of Taxus brevifolia known as Pacific Yew. Yield: 0.015 %. The bark obtained from about 4000 trees yields about one kg of Taxol. The amount isolated from three trees is required from treatment of only one cancer patient.

Sources: 1- Natural. 2- Semisynthesis from Baccatin III. Uses: Breast, Ovarian, lung and other solid tumors. (Antimitotic agent).

Taxol causes the formation of microtubule bundles in HeLa cells Taxol causes the formation of microtubule bundles in HeLa cells. a-tubulin (green) and DNA in the nucleus (blue). (A) Control. (B) 10 mM taxol for 30 min.

Schematic representation of normal Microtubule assembly (upper) and taxol-promoted microtubule assembly (lower).